Robert Mahley, M.D., Ph.D.

JAD profile

Affiliation(s): 

The J. David Gladstone Institutes and the University of California; San Francisco

Lab URL: 

https://gladstone.org/our-science/people/robert-mahley

Areas of Interest: 

Alzheimer's disease, apolipoprotein E

Biography & Research: 

Dr. Robert W. Mahley is a Senior Investigator in the Gladstone Institute of Neurological Disease and President Emeritus/Founder of the Gladstone Institutes. He is a Professor of Pathology and Medicine at the University of California, San Francisco. As President, he oversaw establishment of Gladstone in 1979 and its growth to three institutes, focusing on heart disease, Alzheimer’s disease, and HIV/AIDS. As president-emeritus since 2010, he continues his research in Alzheimer’s disease and other neurodegenerative diseases. His research focuses on heart disease, cholesterol metabolism and Alzheimer’s disease. His seminal research defined the critical role apolipoprotein E (apoE) in cholesterol homeostasis and atherosclerosis. He and his colleagues discovered a unique feature, domain interaction, that differentiates apoE4 structurally and functionally from the neuroprotective apoE3 and apoE2. Because of domain interaction, apoE4 is recognized as an abnormal protein when synthesized by neurons, and it undergoes proteolytic cleavage by a neuron-specific protease generating neurotoxic fragments. ApoE4 fragments escape the secretory pathway and interact with mitochondria, resulting in mitochondrial dysfunction, and with tau, altering the neuronal cytoskeleton neurons. His fundamental contributions to understanding the role of apoE in the nervous system laid the groundwork for the explosion of research linking apoE4 to the pathogenesis of Alzheimer’s disease and neurodegeneration. More recently, Dr. Mahley’s research has focused on potential therapies for Alzheimer’s disease, including the discovery of small molecules that “correct” the structure of apoE4 to be more like apoE3 and, thus, prevent the detrimental effects of apoE4 in cells and animal models of Alzheimer’s disease. He cofounded a new biotech company, E-Scape Bio, Inc., in 2015 to focus on structure correctors. He also serves as CEO/CSO of GABAeron, Inc., a stem cell company. Dr. Mahley’s work has been recognized with many awards and honors. He was elected to the National Academy of Sciences, the National Academy of Medicine, and the American Academy of Arts & Sciences. After earning a BS from Maryville College, Maryville, Tenn., Dr. Mahley completed an MD and a PhD at Vanderbilt University and a pathology internship at Vanderbilt. In 1971, Dr. Mahley joined the staff of the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health and, in 1975, became head of the Comparative Atherosclerosis and Arterial Metabolism Section in NHLBI’s Laboratory of Experimental Atherosclerosis. Four years later, he was recruited to create the Gladstone Institutes.